title: Histone deacetylase 10 promotes autophagy-mediated cell survival.
abstract: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. i.oehme@dkfz.de
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Linke
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Böck
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Marco
authors.initials: M
authors.lastname: Lodrini
authors.forename: Bettina
authors.initials: B
authors.lastname: Hartenstein
authors.forename: Inga
authors.initials: I
authors.lastname: Wiegand
authors.forename: Christian
authors.initials: C
authors.lastname: Eckert
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kaden
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.forename: Sven
authors.initials: S
authors.lastname: Lindner
authors.forename: Anne
authors.initials: A
authors.lastname: Hamacher-Brady
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Brady
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
mesh_terms: D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018840:HSP70 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C447828:HDAC10 protein, human; D006655:Histone Deacetylases
keywords: HDAC inhibitor; childhood tumors; drug resistance